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A novel role for osteopontin in macrophage-mediated amyloid-? clearance in Alzheimer's models.

ABSTRACT: Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115+ monocytes (MoBM) curbs amyloid ?-protein (A?) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated A? clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal A? burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted MoBM further increased OPN levels surrounding residual A? plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP+- or Iba1+-CD45high monocyte-derived macrophages engulfing A? plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115+CD11b+Ly6Chigh) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11b+Ly6C+CD45high monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and A?-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (M?BM). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of A? fibrils and surface scavenger receptors) and anti-inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and A?-degrading enzyme MMP-9). Inhibition of OPN expression in M?BM, either by siRNA, knockout (KOOPN), or minocycline, impairs uptake of A? fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired A? phagocytosis in KOOPN-M?BM. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of A?.

SUBMITTER: Rentsendorj A

PROVIDER: S-EPMC5865478 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models.

Rentsendorj Altan A Sheyn Julia J Fuchs Dieu-Trang DT Daley David D Salumbides Brenda C BC Schubloom Hannah E HE Hart Nadav J NJ Li Songlin S Hayden Eric Y EY Teplow David B DB Black Keith L KL Koronyo Yosef Y Koronyo-Hamaoui Maya M

Brain, behavior, and immunity 20170830

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115<sup>+</sup> monocytes (Mo<sup>BM</sup>) curbs amyloid β-protein (Aβ) neuropathology and preserves cognitive function in murine models of Alzheim ...[more]

PMID: 28860067

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Project description:The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/-). However, the reduction of Aβ load in APP/PS1;cofilin+/- mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin+/- mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation via dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance.

Dataset Information

A novel role for osteopontin in macrophage-mediated amyloid-? clearance in Alzheimer's models.

Publications

A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models.

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